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Prof. Dr. Marco Milanesio

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Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel 11, 15121 Alessandria, Italy
Interests: X-ray diffraction; crystallography; materials science; chemistry; molecular complexes; intermolecular interactions; solid-state chemistry

Special Issue Information

Dear Colleagues,

As crystallographers, we are aware that serendipity sometimes plays a major role in the preparation of new molecular compounds. On the one hand, while many new structures are obtained via crystal engineering and/or accurate experimental design, and theoretical predictions are translated in the production of real crystals, chemistry does not stop surprising us with unexpected molecular structures obtained as byproducts, the degradation of synthesis ingredients, undesired reactions, and inert solvents. On the other hand, many simple molecules used as reactants, synthons and building blocks still have unknown molecular structures because of the difficulty in obtaining suitable single crystals and/or the lack of attempts in producing their crystallizations. All these structures represent a gap in molecular structural knowledge whereby new avenues for new molecular compounds in the form of single molecules, organometallic assemblies and molecular complexes can be explored. Authors are encouraged to demonstrate how these structures are obtained via unconventional routes and/or multi-technique methods and how they can shed new light on molecular material preparation.

Prof. Dr. Marco Milanesio
Guest Editor

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Research

19 pages, 3146 KB

Open AccessArticle

Polymorph Selection and Derivatization in Enantiomerically Pure Medicarpin: Crystallographic and Computational Insights

by Santiago José Guevara-Martínez, Rafael Herrera-Bucio, Marco Antonio Pérez-Cisneros, Gilberto Velázquez-Juárez, Fredy Geovannini Morales-Palacios and Stephanie García-Zavala

Molecules 2025, 30(17), 3652; https://doi.org/10.3390/molecules30173652 - 8 Sep 2025

Viewed by 796

Abstract

Polymorphism critically influences the solid-state properties of organic molecules, affecting stability, solubility, and functionality. We investigated the polymorphic behavior of enantiomerically pure (+)-(6aS,11aS)-medicarpin through combined experimental and computational analyses. Single-crystal X-ray diffraction revealed two distinct chiral polymorphs: the previously reported monoclinic P2₁ form and a newly identified orthorhombic P2₁2₁2₁ form with a fully chiral packing arrangement. The discovery of this previously unreported polymorph underscores the subtle yet decisive effects of solvent and conformational flexibility in directing crystallization. Detailed structural analysis reveals that, whereas the P2₁ form is only stabilized by a single dominant electrostatic interaction, the P2₁2₁2₁ form features a more complex network comprising C-H···π contacts, bifurcated C-H···O hydrogen bonds, and aromatic edge-to-face interactions. Further investigation of a functionalized p-nitrobenzoate derivative corroborates the critical influence of molecular substituents and crystallization conditions on packing motifs. Lattice energy DFT calculations confirm that each polymorph is stabilized by distinct electrostatic and dispersive interaction patterns, illustrating the complex energetic landscape of polymorph selection. Altogether, this work provides a framework for understanding and anticipating which polymorph is likely to form under specific solvent and crystallization conditions, offering insights for future strategies in materials design and guiding the pursuit of patentable crystalline forms in pharmaceutical applications. Full article

(This article belongs to the Special Issue Crystal Structures of Tricky, Unexpected, Labile or Difficult Molecular Structures by Diffraction Methods)

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15 pages, 4657 KB

Open AccessArticle

Conformational and Intermolecular Interaction Analysis of Tiaprofenic Acid: A X-Ray Powder Diffraction and First Principle Modeling Analysis

by Mattia Lopresti, Luca Palin and Marco Milanesio

Molecules 2025, 30(17), 3593; https://doi.org/10.3390/molecules30173593 - 2 Sep 2025

Viewed by 864

Abstract

(±)-tiaprofenic acid (TA), marketed as (Surgam^®), belongs to the family of NSAIDs, with the peculiarity of a reduced incidence of ulcer induction in rats compared with parent drugs. However, some adverse effects were observed, and better knowledge of its interaction with biologic substrates is needed. Unfortunately, unlike most commercial NSAIDs, suitable single crystals for an X-ray diffraction study could not be obtained. To fill the gap, the crystal structure of TA was solved by X-ray powder diffraction, and the molecular interactions stabilizing the structure were analyzed by Hirshfeld surface and energy framework analysis. TA crystallizes in the

P 2_{1} / c

space group, with its two enantiomers in the asymmetric unit, further confirming the peculiarity of the crystal structure and the difficulty of solving it. TA packing is characterized by alternating enantiomers connected through hydrogen bonds, forming chains, arranged in layers, stabilized by

π

-stacking. First principle modeling revealed several stable conformations within 4

k

J

{mol}^{- 1}

of the global minimum and the relaxed potential energy scans revealed modest (8

k

J

{mol}^{- 1}

to 15

k

J

{mol}^{- 1}

) energy barriers. Such flat energy landscape suggests flexible and dynamic behavior of tiaprofenic acid in solution and in vivo conditions, with multiple suitable docking sites. Full article

(This article belongs to the Special Issue Crystal Structures of Tricky, Unexpected, Labile or Difficult Molecular Structures by Diffraction Methods)

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